Serotonin N-acethyltransferase Regulation & Inhibition

血清素 N-乙酰转移酶调节

• 批准号: 7198092
• 负责人: PHILIP A COLE
• 金额: $ 19.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198092
• 关键词: 4' -phosphopantetheine; Acids; Affect; Aging-Related Process; Amino Acids; Anabolism; Arylalkylamine N-Acetyltransferase; Binding; C-terminal; Catalysis; Cells; Chemicals; Circadian Rhythms; Class; Complex; Cultured Cells; Development; Disease; Enzyme Stability; Enzymes; Event; Fluorescence Resonance Energy Transfer; Functional disorder; Generations; Goals; Health; Hormones; Human; Image; Indoles; Kinetics; Lead; Life; Light; Masks; Melatonin; Metabolic; Metabolic Biotransformation; Methods; Modification; Mood Disorders; Moods; Mutagenesis; Neurotransmitters; Phosphorylation; Phosphoserine; Phosphothreonine; Physiology; Pineal gland; Process; Prodrugs; Production; Property; Protein Dephosphorylation; Protein phosphatase; Proteins; Rate; Regulation; Role; Serotonin; Site; Sleep; Sleep Wake Cycle; Time; alkyltransferase; analog; base; crosslink; dephosphocoenzyme A; design; falls; human NAT2 protein; hydroxy compound; in vivo; indole; inhibitor/antagonist; inorganic phosphate; novel; phosphonate; research study; response; tool

DESCRIPTION (provided by applicant): This proposal is a competing renewal application that concerns the regulation, development of synthetic inhibitors, and catalytic mechanism of serotonin N-acetyltransferase, the melatonin rhythm enzyme. Melatonin is circadian rhythm hormone produced in the pineal gland that is hypothesized to contribute to the regulation of sleep-wake cycle, mood, and the process of aging. Precise details about the role of melatonin in physiology and pathophysiology are still lacking, in part because of a dearth of pharmacologic tools. The biosynthesis of melatonin from the neurotransmitter serotonin involves two enzymatic steps, the first of which is catalyzed by serotonin N-acetyltransferase. The diurnal and light-sensitive fluctuation in serotonin Nacetyltransferase drives the rise and fall of melatonin production, the level of which is highest at night. This proposal has three principal goals. First, we plan to develop and characterize a novel class of potent pantetheinyl-prodrug inhibitors of serotonin N-acetyltransferase that promise to be more potent and less toxic than first generation inhibitors. Second, we will elucidate the impact of phosphorylation of serotonin N-acetyltransferase on the cellular stability of the enzyme. Serotonin N-acetyltransferase is known to be phosphorylated on both its N-and C-termini in response to light, but the complete significance of each of these phosphorylation events is not yet known. By incorporating non-hydrolyzable phosphono amino acid analogs in place of phosphothreonine and phosphoserine into serotonin N-acetyltransferase, the precise role of phosphorylation should be revealed. Third, we will clarify the effects of 14-3-3 protein recruitment on the catalytic properties of serotonin N-acetyltransferase. Since the predominant in vivo form of serotonin Nacetyltransferase is probably complexed with 14-3-3, these studies will permit characterization of the physiologically relevant form of this enzyme. It is expected that these studies will lead to an increase in our understanding about the role of melatonin in health and disease and that newly designed inhibitors may serve as lead agents for the treatment of sleep and mood disorders.

描述（由申请人提供）：该提案是涉及涉及5-羟色胺N-乙酰基转移酶，褪黑激素节律酶的调节，合成抑制剂的开发以及催化机制的竞争更新应用。褪黑激素是松果体中产生的昼夜节律激素，假设有助于调节睡眠效果周期，情绪和衰老过程。关于褪黑激素在生理和病理生理学中的作用的精确细节仍然缺乏，部分原因是缺乏药理工具。神经递质5-羟色胺的褪黑激素的生物合成涉及两个酶促步骤，其中第一个是由5-羟色胺N-乙酰基转移酶催化的。 5-羟色胺nacetylstransferase中的昼夜和光敏性波动驱动褪黑激素产生的兴起和下降，其水平在夜间最高。该提议有三个主要目标。首先，我们计划开发和表征一类新型的5-羟色胺N-乙酰转移酶的有效panteheinyl-prodrug抑制剂，该抑制剂承诺比第一代抑制剂更有效，更毒性。其次，我们将阐明5-羟色胺N-乙酰转移酶对酶细胞稳定性的影响。已知羟色胺N-乙酰转移酶在其N和C末端都响应光的N和C末端都被磷酸化，但是这些磷酸化事件的完全重要性尚不清楚。通过将不可氢化的磷酸氨基酸类似物掺入磷酸硫氨酸和磷酸氨酸中，应揭示磷酸化的确切作用。第三，我们将阐明14-3-3蛋白募集对5-羟色胺N-乙酰基转移酶催化特性的影响。由于5-羟色胺nacetyltransferase的体内主要形式可能与14-3-3复合，因此这些研究将允许表征该酶的生理相关形式。预计这些研究将导致我们对褪黑激素在健康和疾病中的作用的理解有所提高，而新设计的抑制剂可能是治疗睡眠和情绪障碍的主要药物。